It is now widely accepted that inflammation is a key component of the etiology of obesity-linked insulin resistance leading the way to type 2 diabetes mellitus (T2DM) (Wellen and Hotamisligil, 2005; White and Marette, 2008). Novel anti-inflammatory compounds are therefore of great interest to the field. The enzymatic oxidation of omega-3 (ω-3) polyunsaturated fatty acids (PUFA) yields multiple families of bioactive lipids, which include the resolvins, protectins and maresins (Norling and Serhan, 2010). These novel lipid mediators possess potent anti-inflammatory activity owing to their role in the active termination of endogenous inflammation; however, their therapeutic potential for the treatment of metabolic disorders such as insulin resistance remains to be demonstrated.
Using fat-1 transgenic mice that are characterized by elevated tissue ω-3 content (Kang et al., 2004), we recently demonstrated that greater endogenous biosynthesis of protectin D1 in adipose tissue and skeletal muscle of high fat fed obese mice is associated with an improved global resolution capacity, reduced inflammation and protection from insulin resistance (White et al., 2010).
Protectin D1 (PD1), identified as 10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid, is the most studied member of the protectin family (Serhan et al., 2006). PD1 is derived from 12/15-lipoxygenase mediated oxygenation of docosahexaenoic acid (DHA; 22:6 n-3) followed by epoxidation and reduction of the 17S-hydroperoxy DHA intermediate (Serhan et al., 2006). A natural stereoisomer of PD1, 10S,17S-dihydroxy-docosa-4Z,7Z,11E,13Z,15E,19Z-hexaenoic acid, first described as compound I (Serhan et al., 2006) and recently designated Protectin DX (PDX) (Chen et al., 2009) is also present in vivo. PDX is produced via sequential lipoxygenation of DHA and differs from PD1 with respect to the double bond geometry of carbons 13 and 15 as well as the position of the C-10 hydroxyl (Chen et al., 2009; Serhan et al., 2006). PDX is found alongside PD1 in murine inflammatory exudates and may also be produced by human neutrophils exposed to DHA, albeit to a lesser extent than PD1 (Serhan et al., 2006). To the best of our knowledge the influence of protectins on insulin sensitivity and glucose metabolism has not yet been examined.
The prior art is replete with data indicating that IL-6 is decreased following the administration of molecules from the Resolvin/Protectin families (Schwab et al. 2007; Aksam et al. 2008; Hawort et al. 2008, Liao et al. 2012; Das 2012).
Herein is provided a first evidence of the therapeutic potential of PDX for lipid-induced inflammation and insulin resistance. Importantly, we reveal an unanticipated mechanism of action whereby PDX enhances both hepatic and peripheral glucose metabolism in vivo by increasing the prototypic myokine IL-6.